FURTHER GUIDANCE ON A DATA AND SAFETY MONITORING FOR PHASE I AND PHASE II TRIALS
Release Date: June 5, 2000
NOTICE: OD-00-038
National Institutes of Health
Policy: Beginning with the October 2000 receipt date, investigators
must submit a monitoring plan for phase I and II clinical trials to the
funding Institute and Center (IC) before the trial begins.
Background
In June 1998, the National Institutes of Health (NIH) issued a policy
on data and safety monitoring
(http://grants.nih.gov/grants/guide/notice-files/not98-084.html) that
requires oversight and monitoring of all intervention studies to ensure
the safety of participants and the validity and integrity of the data.
The policy further elaborates that monitoring should be commensurate
with risks and with the size and complexity of the trials. The NIH
already requires data and safety monitoring, generally, in the form of
Data and Safety Monitoring Boards (DSMBs) for phase III clinical
trials. For earlier trials (phase I and II), a DSMB may be appropriate
if the studies have multiple clinical sites, are blinded (masked), or
employ particularly high-risk interventions or vulnerable populations.
This document provides further guidance for monitoring of phase I and
II trials. This guidance does not take the place of Institutional
Review Board (IRB) guidelines, Food and Drug Administration (FDA)
requirements, or special NIH guidelines e.g., NIH Guidelines for
Research Involving Recombinant DNA Molecules. Specifically, phase I
and II gene transfer trials must comply with additional requirements
imposed by the latter NIH Guidelines, e.g., reporting of adverse events
to the Office of Biotechnology Activities.
Monitoring plan
For phase I and II clinical trials, investigators must submit a general
description of the data and safety monitoring plan as part of the
research application. This plan will be reviewed by the scientific
review group and any comments and concerns will be included in an
administrative note in the summary statement. A detailed monitoring
plan, however, must be included as part of the protocol and submitted
to the local IRB and reviewed and approved by the funding Institute and
Center (IC) before the trial begins. We strongly encourage the IRB to
review the plan. Each IC should have a system for appropriate
oversight and monitoring of the conduct of clinical trials to ensure
the safety of participants and the validity and integrity of the data.
IC oversight of the monitoring activities is distinct from the
monitoring itself. Oversight of monitoring must be done to ensure that
monitoring plans are in place for all phase I or II trials and that the
IC is informed of recommendations and any necessary actions that
emanate from the monitoring activities.
At a minimum, all monitoring plans must include a description of the
reporting mechanisms of adverse events to the IRB, the FDA and the NIH.
Investigators must ensure that the NIH is informed of actions, if any,
taken by the IRB as a result of its continuing review. ICs have the
flexibility to determine the reporting requirements of adverse events.
The reporting requirement to the NIH may range from individual adverse
event reports to summary reports from the monitoring group. In specific
cases where the funding IC is the sponsor of the test agent, i.e.,
holder of the Investigational New Drug (IND) application, investigators
must submit individual adverse event reports to the IC (as sponsor) in
accordance with FDA regulations. Occasionally, there are phase I or II
trials that have established safety monitoring committees. In these
cases, summary reports of the committees’ discussions of adverse events
must be submitted to the IC and IRB. The reporting requirements for
adverse events, as approved by the ICs, are in addition to the annual
progress reports to the NIH for type 5 awards (non-competing awards).
The overall elements of the monitoring plan may vary depending on the
potential risks, complexity, and nature of the trial. In phase I and
II trials, a number of factors influence risk. A phase I trial of a new
drug or agent may involve increasing risk, to a small number of
participants, as the drug is escalated in dosage. For phase II trials,
there is sometimes information about risks in normal subjects, but risk
may be increased as more participants are involved and the toxicity and
outcomes may be confounded by the disease process. In situations
involving potentially high risks or special populations, investigators
must consider additional monitoring safeguards.
For many phase I and phase II trials, independent DSMBs may not be
necessary or appropriate when the intervention is low risk.
Continuous, close monitoring by the study investigator may be an
adequate and appropriate format for monitoring, with prompt reporting
of toxicity to the IRB, FDA and/or NIH. In some instances, the study
investigator or the IRB may determine that an independent individual
may be needed for monitoring. In studies of small numbers of subjects,
toxicity may more readily become apparent through close monitoring of
individual patients, while in larger studies risk may better be
assessed through statistical comparisons of treatment groups.
For multisite phase I and II trials, study investigators should
organize a central reporting entity that will be responsible for
preparing timely summary reports of adverse events for distribution
among sites and the IRBs. The frequency of the summary reports will
depend on the nature of the trials. Additional NIH guidance for
reporting adverse events for multisite clinical trials with a DSMB has
been published in 1999. (See
http://grants.nih.gov/grants/guide/notice-files/not99-107.html)
Grantee institutions with a large number of clinical trials may develop
standard monitoring plans for phase I and II trials. Thus, individual
study investigators will be able to include the IRB-approved monitoring
plan in their submission to the NIH. However, such plans should
always be evaluated for appropriateness to the particular
investigation.